Guidelines for minimal information on cellular senescence experimentation in vivo.

Cellular senescence is a cell fate triggered in response to stress and is characterized by stable cell-cycle arrest and a hypersecretory state. It has diverse biological roles, ranging from tissue repair to chronic disease. The development of new tools to study senescence in vivo has paved the way for uncovering its physiological and pathological roles and testing senescent cells as a therapeutic target. However, the lack of specific and broadly applicable markers makes it difficult to identify and characterize senescent cells in tissues and living organisms. To address this, we provide practical guidelines called "minimum information for cellular senescence experimentation in vivo" (MICSE). It presents an overview of senescence markers in rodent tissues, transgenic models, non-mammalian systems, human tissues, and tumors and their use in the identification and specification of senescent cells. These guidelines provide a uniform, state-of-the-art, and accessible toolset to improve our understanding of cellular senescence in vivo.

Apoptotic stress causes mtDNA release during senescence and drives the SASP.

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.

Neutrophils induce paracrine telomere dysfunction and senescence in ROS-dependent manner.

Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro-inflammatory phenotype, thought to contribute to aging and age-related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age-related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non-immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS-dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by which senescence spreads to surrounding cells. Our results suggest that interventions that counteract neutrophil-induced senescence may be beneficial during aging and age-related disease.

Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span.

Senescence is the consequence of a signaling mechanism activated in stressed cells to prevent proliferation of cells with damage. Senescent cells (Sncs) often develop a senescence-associated secretory phenotype to prompt immune clearance, which drives chronic sterile inflammation and plays a causal role in aging and age-related diseases. Sncs accumulate with age and at anatomical sites of disease. Thus, they are regarded as a logical therapeutic target. Senotherapeutics are a new class of drugs that selectively kill Sncs (senolytics) or suppress their disease-causing phenotypes (senomorphics/senostatics). Since 2015, several senolytics went from identification to clinical trial. Preclinical data indicate that senolytics alleviate disease in numerous organs, improve physical function and resilience, and suppress all causes of mortality, even if administered to the aged. Here, we review the evidence that Sncs drive aging and disease, the approaches to identify and optimize senotherapeutics, and the current status of preclinical and clinical testing of senolytics.

A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. CONCLUSIONS: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.

Marrow Adipocyte Senescence in the Pathogenesis of Bone Loss.

PURPOSE OF REVIEW: Beyond aging, senescent cells accumulate during multiple pathological conditions, including chemotherapy, radiation, glucocorticoids, obesity, and diabetes, even earlier in life. Therefore, cellular senescence represents a unifying pathogenic mechanism driving skeletal and metabolic disorders. However, whether senescent bone marrow adipocytes (BMAds) are causal in mediating skeletal dysfunction has only recently been evaluated. RECENT FINDINGS: Despite evidence of BMAd senescence following glucocorticoid therapy, additional evidence for BMAd senescence in other conditions has thus far been limited. Because the study of BMAds presents unique challenges making these cells difficult to isolate and image, here we review issues and approaches to overcome such challenges, and present advancements in isolation and histological techniques that may help with the future study of senescent BMAds. Further insights into the roles of BMAd senescence in the pathogenesis of skeletal dysfunction may have important basic science and clinical implications for human physiology and disease.

Vertebral Fracture Risk Thresholds from Phantom-Less Quantitative Computed Tomography-Based Finite Element Modeling Correlate to Phantom-Based Outcomes.

INTRODUCTION: Osteoporosis indicates weakened bones and heightened fracture susceptibility due to diminished bone quality. Dual-energy x-ray absorptiometry is unable to assess bone strength. Volumetric bone mineral density (vBMD) from quantitative computed tomography (QCT) has been used to establish guidelines as equivalent measurements for osteoporosis. QCT-based finite element analysis (FEA) has been implemented using calibration phantoms to establish bone strength thresholds based on the established vBMD. The primary aim was to validate vertebral failure load thresholds using a phantom-less approach with previously established thresholds, advancing a phantom-free approach for fracture risk prediction. METHODOLOGY: A controlled cohort of 108 subjects (68 females) was used to validate sex-specific vertebral fracture load thresholds for normal, osteopenic, and osteoporotic subjects, obtained using a QCT/FEA-based phantom-less calibration approach and two material equations. RESULTS: There were strong prediction correlations between the phantom-less and phantom-based methods (R2: 0.95 and 0.97 for males, and R2: 0.96 and 0.98 for females) based on the two equations. Bland Altman plots and paired t-tests showed no significant differences between methods. Predictions for bone strengths and thresholds using the phantom-less method matched those obtained using the phantom calibration and those previously established, with ≤4500 N (fragile) and ≥6000 N (normal) bone strength in females, and ≤6500 N (fragile) and ≥8500 N (normal) bone strength in males. CONCLUSION: Phantom-less QCT-based FEA can allow for prospective and retrospective studies evaluating incidental vertebral fracture risk along the spine and their association with spine curvature and/or fracture etiology. The findings of this study further supported the application of phantom-less QCT-based FEA modeling to predict vertebral strength, aiding in identifying individuals prone to fractures. This reinforces the rationale for adopting this method as a comprehensive approach in predicting and managing fracture risk.

Reference Intervals for Bone Impact Microindentation in Healthy Adults: A Multi-Centre International Study.

Impact microindentation (IMI) is a novel technique for assessing bone material strength index (BMSi) in vivo, by measuring the depth of a micron-sized, spherical tip into cortical bone that is then indexed to the depth of the tip into a reference material. The aim of this study was to define the reference intervals for men and women by evaluating healthy adults from the United States of America, Europe and Australia. Participants included community-based volunteers and participants drawn from clinical and population-based studies. BMSi was measured on the tibial diaphysis using an OsteoProbe in 479 healthy adults (197 male and 282 female, ages 25 to 98 years) across seven research centres, between 2011 and 2018. Associations between BMSi, age, sex and areal bone mineral density (BMD) were examined following an a posteriori method. Unitless BMSi values ranged from 48 to 101. The mean (± standard deviation) BMSi for men was 84.4 ± 6.9 and for women, 79.0 ± 9.1. Healthy reference intervals for BMSi were identified as 71.0 to 97.9 for men and 59.8 to 95.2 for women. This study provides healthy reference data that can be used to calculate T- and Z-scores for BMSi and assist in determining the utility of BMSi in fracture prediction. These data will be useful for positioning individuals within the population and for identifying those with BMSi at the extremes of the population.

Influences of Aged Bone Marrow Macrophages on Skeletal Health and Senescence.

PURPOSE OF REVIEW: The purpose of this review is to discuss the role of macrophages in the regulation of skeletal health with age, particularly in regard to both established and unexplored mechanisms in driving inflammation and senescence. RECENT FINDINGS: A multitude of research has uncovered mechanisms of intrinsic aging in macrophages, detrimental factors released by these immune cells, and crosstalk from senescent mesenchymal cell types, which altogether drive age-related bone loss. Furthermore, bone marrow macrophages were recently proposed to be responsible for the megakaryocytic shift during aging and overall maintenance of the hematopoietic niche. Studies on extra-skeletal macrophages have shed light on possible conserved mechanisms within bone and highlight the importance of these cells in systemic aging. Macrophages are a critically important cell type in maintaining skeletal homeostasis with age. New discoveries in this area are of utmost importance in fully understanding the pathogenesis of osteoporosis in aged individuals.

Guanylyl Cyclase-B Dependent Bone Formation in Mice is Associated with Youth, Increased Osteoblasts, and Decreased Osteoclasts.

C-type natriuretic peptide (CNP) activation of guanylyl cyclase-B (GC-B) catalyzes the synthesis of cGMP in chondrocytes and osteoblasts. Elevated cGMP stimulates long bone growth, and inactivating mutations in CNP or GC-B reduce cGMP, which causes dwarfism. GC-B7E/7E mice that express a GC-B mutant that cannot be inactivated by dephosphorylation exhibit increased CNP-dependent GC-B activity, which increases bone length, as well as bone mass and strength. Importantly, how GC-B increases bone mass is not known. Here, we injected 12-week-old, wild type mice once daily for 28 days with or without BMN-111 (Vosoritide), a proteolytically resistant CNP analog. We found that BMN-111 treated mice had elevated levels of osteocalcin and collagen 1 C-terminal telopeptide (CTX) as well as increased osteoblasts and osteoclasts. In BMN-111 injected mice, tibial mRNAs for Rank ligand and osteoprotegrin were increased and decreased, respectively, whereas sclerostin mRNA was elevated 400-fold, consistent with increased osteoclast activity and decreased osteoblast activity. Mineral apposition rates and trabecular bone mass were not elevated in response to BMN-111. Because 9-week-old male GC-B7E/7E mice have increased bone mass but do not exhibit increased mineral apposition rates, we examined 4-week-old male GC-B7E/7E mice and found that these animals had increased serum osteocalcin, but not CTX. Importantly, tibias from these mice had 37% more osteoblasts, 26% fewer osteoclasts as well as 36% and 40% higher mineral apposition and bone formation rates, respectively. We conclude that GC-B-dependent bone formation is coupled to an early juvenile process that requires both increased osteoblasts and decreased osteoclasts.

Pathophysiologic importance of visceral adipose tissue in women with heart failure and preserved ejection fraction.

AIMS: Central obesity is a major risk factor for heart failure with preserved ejection fraction (HFpEF), particularly in women, but the mechanisms remain unclear. We hypothesized that sex-specific differences in visceral adipose tissue (VAT) content would differentially relate to haemodynamic severity of HFpEF in women and men. METHODS AND RESULTS: Abdominal computed tomography (CT) and invasive haemodynamic exercise testing were performed in 105 subjects with HFpEF (63 women) and 105 age-, sex-, and body mass index-matched controls. Visceral adipose tissue area was quantified by CT. As compared with control women, VAT area was 34% higher in women with HFpEF (186 ± 112 vs. 139 ± 72 cm2, P = 0.006), while VAT area was not significantly different in men with or without HFpEF (294 ± 158 vs. 252 ± 92 cm2, P = 0.1). During exercise, pulmonary capillary wedge pressure (PCWP) increased markedly and to similar extent in both men and women with HFpEF. Women with increased VAT area displayed 33% higher PCWP during exercise compared with women with normal VAT area (28 ± 10 vs. 21 ± 10 mmHg, P = 0.001), whereas exercise PCWP was similar in men with or without excess VAT (24 ± 9 vs. 25 ± 6, P = 0.89). In women, each 100 cm2 increase in VAT area was associated with a 4.0 mmHg higher PCWP (95% CI 2.1, 6.0 mmHg; P < 0.0001), but there was no such relationship in men (interaction P = 0.009). CONCLUSIONS: These data suggest that accumulation of excess VAT plays a distinct and important role in the pathophysiology of HFpEF preferentially in women. Further research is needed to better understand the mechanisms and treatment implications for visceral fat in HFpEF.

Opportunistic application of phantom-less calibration methods for fracture risk prediction using QCT/FEA.

OBJECTIVES: Quantitative computed tomography (QCT)-based finite element analysis (FEA) implements a calibration phantom to estimate bone mineral density (BMD) and assign material properties to the models. The objectives of this study were to (1) propose robust phantom-less calibration methods, using subject-specific tissues, to obtain vertebral fracture properties estimations using QCT/FEA; and (2) correlate QCT/FEA predictions to DXA values of areal BMD. METHODS: Eighty of a cohort of 111 clinical QCT scans were used to obtain subject-specific parameters using a phantom calibration approach and for the development of the phantom-less calibration equations. Equations were developed based on the HU measured from various soft tissues and regions, and using multiple linear regression analyses. Thirty-one additional QCT scans were used for cross-validation of QCT/FEA estimated fracture loads from the L3 vertebrae based on the phantom and phantom-less equations. Finally, QCT/FEA-predicted fracture loads were correlated with aBMD obtained from DXA. RESULTS: Overall, 217 QCT/FEA models from 31 subjects (20 females, 11 men) with mean ages of 69.6 (13.1) and 67.3 (14) were used to cross-validate the phantom-less equations and assess bone strength. The proposed phantom-less equations showed high correlations with phantom-based estimates of BMD (99%). Cross-validation of QCT/FEA-predicted fracture loads from phantom-less equations and phantom-specific outcomes resulted in high correlations for all proposed methods (0.94-0.99). QCT/FEA correlation outcomes from the phantom-less equations and DXA-aBMD were moderately high (0.64-0.68). CONCLUSIONS: The proposed QCT/FEA subject-specific phantom-less calibration methods demonstrated the potential to be applied to both prospective and retrospective applications in the clinical setting. KEY POINTS: • QCT/FEA overcomes the disadvantages of DXA and improves fracture properties predictions of vertebrae. • QCT/FEA fracture estimates using the phantom-less approach highly correlated to values obtained using a calibration phantom. • QCT/FEA prediction using a phantom-less approach is an accurate alternative over phantom-based methods.

Unsupervised machine learning for the discovery of latent disease clusters and patient subgroups using electronic health records.

Machine learning has become ubiquitous and a key technology on mining electronic health records (EHRs) for facilitating clinical research and practice. Unsupervised machine learning, as opposed to supervised learning, has shown promise in identifying novel patterns and relations from EHRs without using human created labels. In this paper, we investigate the application of unsupervised machine learning models in discovering latent disease clusters and patient subgroups based on EHRs. We utilized Latent Dirichlet Allocation (LDA), a generative probabilistic model, and proposed a novel model named Poisson Dirichlet Model (PDM), which extends the LDA approach using a Poisson distribution to model patients' disease diagnoses and to alleviate age and sex factors by considering both observed and expected observations. In the empirical experiments, we evaluated LDA and PDM on three patient cohorts, namely Osteoporosis, Delirium/Dementia, and Chronic Obstructive Pulmonary Disease (COPD)/Bronchiectasis Cohorts, with their EHR data retrieved from the Rochester Epidemiology Project (REP) medical records linkage system, for the discovery of latent disease clusters and patient subgroups. We compared the effectiveness of LDA and PDM in identifying disease clusters through the visualization of disease representations. We tested the performance of LDA and PDM in differentiating patient subgroups through survival analysis, as well as statistical analysis of demographics and Elixhauser Comorbidity Index (ECI) scores in those subgroups. The experimental results show that the proposed PDM could effectively identify distinguished disease clusters based on the latent patterns hidden in the EHR data by alleviating the impact of age and sex, and that LDA could stratify patients into differentiable subgroups with larger p-values than PDM. However, those subgroups identified by LDA are highly associated with patients' age and sex. The subgroups discovered by PDM might imply the underlying patterns of diseases of greater interest in epidemiology research due to the alleviation of age and sex. Both unsupervised machine learning approaches could be leveraged to discover patient subgroups using EHRs but with different foci.

Osteocyte Cellular Senescence.

PURPOSE OF REVIEW: Senescent cells are now known to accumulate in multiple tissues with aging and through their inflammation (the senescence-associated secretory phenotype, SASP) contribute to aging and chronic diseases. Here, we review the roles of senescent osteocytes in the context of bone loss. RECENT FINDINGS: Numerous studies have established that senescent osteocytes accumulate in the bone microenvironment with aging in mice and in humans. Moreover, at least in mice, elimination of senescent cells results in attenuation of age-related bone loss. Osteocyte senescence also occurs in response to other cellular stressors, including radiotherapy, chemotherapy, and metabolic dysfunction, where it appears to mediate skeletal deterioration. Osteocyte senescence is linked to bone loss associated with aging and other conditions. Senescent osteocytes are potential therapeutic targets to alleviate skeletal dysfunction. Additional studies better defining the underlying mechanisms as well as translating these exciting findings from mouse models to humans are needed.

Posterior single-stepping thresholds are prospectively related to falls in older women.

BACKGROUND: Falls are a leading cause of injury in older women. Stepping thresholds quantify balance-reaction capabilities. It is unclear how such evaluations predict falls in comparison to, or as a complement to, other objective measures of gait, standing postural control, strength, and balance confidence. AIMS: The objective of this study was to determine if stepping thresholds are prospectively related to falls in older women. METHODS: For this prospective cohort study, 125 ambulatory, community-dwelling women, age ≥ 65 years were recruited. Using a treadmill to deliver perturbations to standing participants, we determined anteroposterior single- and multiple-stepping thresholds. Here, thresholds represent the minimum perturbation magnitudes that consistently evoke one step or multiple steps. In addition, gait kinematics, obstacle-crossing kinematics, standing sway measures, unipedal stance time, the functional reach, lower extremity isometric strength, grip strength, balance confidence, and fall history were evaluated. Falls were prospectively recorded for one year. RESULTS: Seventy-four participants (59%) fell at least once. Posterior single-stepping thresholds were the only outcome that predicted future fall status (OR = 1.50, 95% CI 1.01-2.28; AUC = .62). A multivariate approach added postural sway with eyes closed as a second predictive variable, although predictive abilities were not meaningfully improved. DISCUSSION: These results align with the previous evidence that reactive balance is a prospective indicator of fall risk. Unlike previous studies, strength scaled to body size did not contribute to fall prediction. CONCLUSION: Posterior single-stepping thresholds held a significant relationship with future fall status. This relationship was independent of, and superior to that of, other measures of standing balance, gait, strength, and balance confidence.

Periodontal Disease and Senescent Cells: New Players for an Old Oral Health Problem?

The recent identification of senescent cells in periodontal tissues has the potential to provide new insights into the underlying mechanisms of periodontal disease etiology. DNA damage-driven senescence is perhaps one of the most underappreciated delayed consequences of persistent Gram-negative bacterial infection and inflammation. Although the host immune response rapidly protects against bacterial invasion, oxidative stress generated during inflammation can indirectly deteriorate periodontal tissues through the damage to vital cell macromolecules, including DNA. What happens to those healthy cells that reside in this harmful environment? Emerging evidence indicates that cells that survive irreparable genomic damage undergo cellular senescence, a crucial intermediate mechanism connecting DNA damage and the immune response. In this review, we hypothesize that sustained Gram-negative bacterial challenge, chronic inflammation itself, and the constant renewal of damaged tissues create a permissive environment for the abnormal accumulation of senescent cells. Based on emerging data we propose a model in which the dysfunctional presence of senescent cells may aggravate the initial immune reaction against pathogens. Further understanding of the role of senescent cells in periodontal disease pathogenesis may have clinical implications by providing more sophisticated therapeutic strategies to combat tissue destruction.

Sex-specific effects of dehydroepiandrosterone (DHEA) on bone mineral density and body composition: A pooled analysis of four clinical trials.

OBJECTIVE: Studies of dehydroepiandrosterone (DHEA) therapy in older adults suggest sex-specific effects on bone mineral density (BMD) and body composition, but the ability of a single study to reach this conclusion was limited. We evaluated the effects of DHEA on sex hormones, BMD, fat mass and fat-free mass in older women and men enrolled in four similar clinical trials. DESIGN: Pooled analyses of data from four double-blinded, randomized controlled trials. PARTICIPANTS: Women (n = 295) and men (n = 290) aged 55 years or older who took DHEA or placebo tablet daily for 12 months. MEASUREMENTS: Twelve-month changes in BMD, fat mass, fat-free mass and serum DHEA sulphate (DHEAS), (17)estradiol, testosterone and insulin-like growth factor-1 (IGF-1). RESULTS: Women on DHEA had increases (mean ± SD; all P < 0.001 vs placebo) in DHEAS (231 ± 164 µg/dL), testosterone (18.6 ± 20.9 µg/dL), (17)estradiol (8.7 ± 11.0 pg/mL) and IGF-1 (25.1 ± 52.3 ng/mL), and men had increases in DHEAS (269.0 ± 177 µg/dL; P < 0.01), (17)estradiol (4.8 ± 12.2 pg/m; P < 0.01) and IGF-1 (6.3 ± 41.4 ng/mL; P < 0.05). Women on DHEA had increases in lumbar spine (1.0% ± 3.4%) and trochanter (0.5% ± 3.8%) BMD and maintained total hip BMD (0.0% ± 2.8%); men had no BMD benefit and a decrease in fat mass (-0.4 ± 2.6 kg; all P < 0.01 vs placebo). CONCLUSIONS: Dehydroepiandrosterone therapy may be an effective approach for preserving bone and muscle mass in women. Key questions are (a) the extent to which longer duration DHEA can attenuate the loss of bone and muscle in women, and (b) whether DHEA has a more favourable benefit-to-risk profile for women than oestrogen therapy.

Proceedings of the 2018 Santa Fe Bone Symposium: Advances in the Management of Osteoporosis.

The Santa Fe Bone Symposium is an annual meeting devoted to clinical applications of recent advances in skeletal research. The 19th Santa Fe Bone Symposium convened August 3-4, 2018, in Santa Fe, New Mexico, USA. Attendees included physicians of many specialties, fellows in training, advanced practice providers, clinical researchers, and bone density technologists. The format consisted of lectures, case presentations by endocrinology fellows, and panel discussions, with all involving extensive interactive discussions. Topics were diverse, including an evolutionary history of calcium homeostasis, osteoporosis treatment in the very old, optimizing outcomes with orthopedic surgery, microbiome and bone, new strategies for combination and sequential therapy of osteoporosis, exercise as medicine, manifestations of parathyroid hormone excess and deficiency, parathyroid hormone as a therapeutic agent, cell senescence and bone health, and managing patients outside clinical practice guidelines. The National Bone Health Alliance conducted a premeeting on development of fracture liaison services. A workshop was devoted to Bone Health TeleECHO (Bone Health Extension for Community Healthcare Outcomes), a strategy of ongoing medical education for healthcare professions to expand capacity to deliver best practice skeletal healthcare in underserved communities and reduce the osteoporosis treatment gap.

New hope for symptom management during natural and iatrogenic menopause transitions.

Bone loss is associated with aging and is exacerbated by female transition to menopause. Estrogen has long been associated with bone loss, and replacement therapy is effective at restoring bone health. In the last 10 years, pituitary and gonadal peptide hormones have been implicated in bone biology, and here we update the story on FSH and its potential role as a direct regulator of bone and adipose. If translated to humans, new approaches to ameliorate age related bone demise could be developed. Moreover, young women with hormone responsive cancers who are unable to maintain bone may have new routes to avoid debilitating bone loss.